In many therapeutic programs pertaining to the management of health and disease, the use of drug delivery devices which provide for the slow release of a drug to the body at a controlled rate over a prolonged period of time to achieve a desired physiologic or pharmacologic effect has proved beneficial. A principal advantage of employing sustained-release compositions is that many therapeutic agents would otherwise be rapidly metabolized or cleared from the patient's system necessitating frequent administration of the drug to maintain a therapeutically effective concentration.
Accordingly, a variety of sustained release devices have been designed for oral, rectal and subcutaneous administration. "Matrix" type devices typically consist of an active compound dispersed in a matrix of carrier material which may be either porous or non-porous, solid or semi-solid, and permeable or impermeable to the active compound. These devices are rather easily prepared; however, they are not suitable for administering some pharmacologically active compounds. In addition, the rate of release of the active compound decreases with time. "Reservoir" type devices consist of a central reservoir of active compound surrounded by a rate controlling membrane (rcm). The rcm is generally a porous or a non-porous material which is non-biodegradable. In the case of the transdermal devices of this type, to maintain an effective concentration of active compound, the rate controlling membrane must have a large surface area. Thus, a common disadvantage of these devices is that their large size makes administration quite inconvenient. Other sustained release devices are hybrid-type devices which contain a matrix core surrounded by a rcm. Yet other devices are mechanical in nature, and include active compound-filled electrical or osmotic pumps. These devices require frequent replacement. In addition, they have proved to be too large and expensive to be practical.
There has been a consistently large demand for the development of new, long-acting contraceptives that require minimal medical guidance. This is particularly the case in less developed countries where medical and family planning organizations are inadequate. Accordingly, several contraceptive implant systems (used hereinafter interchangeably with "devices") have been developed. For example, the Norplant.RTM. system contains six 3.4 cm capsules, each containing crystals of the synthetic progestin, levonorgestrel. When implanted subdermally, levonorgestrel diffuses through the polydimethylsiloxane (Silastic.RTM.) capsules. The contraceptive agent, 16-methylene-17.alpha.-acetoxy-19-nor-4-pregnene-3, 20 dione, or 16-methylene-17-.alpha.-acetone-19-norprogesterone (Nestorone.TM.), has also been used in similar devices. See Coutinho et al., Int. J. Fertil. Steril. 21:103-08 (1976). However, such contraceptive capsules have been criticized as being too short-lived and thus unsuitable for long-term contraception. See, e.g., Coutinho et al., Fertil. Steril. 36:737-40 (1981) (disclosing that the implants had to be changed after six months); and Lahteenmaki et al., Contraception 25:299-306 (1982) and Odlind et al., "Development of an Implant," in Zatuchni et al. (eds), Long-Acting Contraceptive Delivery Systems, Philadelphia, Harper and Row, pp. 441-49 (1984) (both reporting that the silastic implants were exhausted in less than one year). Subsequently, the Norplant II contraceptive system was developed. The Norplant II system contains two 4 cm implants, which together deliver a contraceptive effective dose of levonorgestrel for at least three years. Each implant consists of a rod-shaped drug matrix encased in a Silastic.RTM. tube sealed at both ends with an adhesive. Sujan et al., Contraception 50:27-34 (1994). Although the Silastic.RTM. provides excellent biological compatibility with bodily fluids and tissues, they have also been found to allow for a rather high permeability to certain steroids.
It has been reported that the levonorgestrel present in the Norplant II system displays androgenic and hormonal side effects. See, e.g., Haukkamaa et al., Contraception 45(1):49-55 (1992). Such side effects may be mitigated by the selection of other progestins such as the Nestorone.TM. progestin. However, the fact that this progestin is inactive when administered orally underscores the need to provide subdermally implantable contraceptive devices which are free of the disadvantages associated with prior art devices.
Although the ideal contraceptive implant may elude precise definition, there is general agreement in the field that the design of such an implant is complicated by several interrelated factors. First, the system must administer effective contraception for a period of at least about two years, and preferably about from 4 to 5 years, yet while at the same time minimizing the number of implants. The number of implants has been constrained by the amount of contraceptive agent needed, which in turn is dependent upon the potency of the chosen contraceptive agent. In addition, the device must release the contraceptive agent at a substantially constant rate (i.e., zero-order release) so as to avoid initial overdosing and depletion of the agent prior to the expiration of its intended useful lifetime. This factor is influenced by the solubility of the contraceptive agent in the various compartments of the device, the rate of diffusion of the active agent from the device, the surface area of the device, and the rate of removal of the active agent from bodily tissue surrounding the outer surface of the device. Further, the dimensions of the implant must be determined not only to take into account the release rate of the contraceptive, but also to impart the necessary rigidity to the device to facilitate its implantation. Even further, the device must be non-irritating and produce minimal side effects, as well as mechanically strong to withstand flexion or impact. Hence, a need remains for a subdermally implantable contraceptive device which fulfills at least some of these existing needs.